DESCRIPTION: This proposal will explore cellular and molecular mechanisms to induce mucosal and systemic immune responses specific for SIV and HIV through the nasal-associated lymphoreticular tissue (NALT). They will employ non-toxic cholera-toxin mutants as adjuvants in combination with SIV gp130 or HIV gp160 delivered intranasally as a means to understand the induction pathways in both mice and humans. In a separate proposal, they aim to conduct similar studies SIV/macaque model. In Aim 1, the applicant will characterize murine NALT and associated mucosal tissues after nasal immunization with SIV gp130 (or HIV gp160) with mCT and develop an in vitro human NALT system to assess mCT-induced antigen uptake. In Aim 2, signal transduction pathways of NALT antigen-specific CD4+ T cells will be analyzed following nasal immunization. In Aim 3, they will develop and characterize chimeric mCTs which can mimic induction of antigen-specific Th1 or Th2 type responses following nasal immunization. In Aim 4, they will assess the effects of mCTs on antigen-presenting cells from human tonsils and adenoids for potentiation of Th1-or Th2-type responses. In Aim 5, they will determine the safety and immunogenicity of a combined gp160 and mCT nasal vaccine in humans in a phase I vaccine trial.